To determine whether cytomegalovirus (CMV) infection evokes diverse immune responses, we found that different immunodominant phenotypes against CMV infection are present in immunocompetent individuals. Four types of patterns were observed in 50 healthy individuals: 1) neither anti-CMV IgG antibodies (Ab) nor a T-cell proliferative response (Tc) to CMV antigens (Ab-/Tc-; 30%), indicating no existing immunologic evidence of prior CMV exposure; 2) antibody responses without T-cell responses (Ab+/Tc-; 24%); 3) responses by both arms of the immune system (Ab+/Tc+; 18%); and, surprisingly, 4) T-cell responses in the absence of detectable antibodies to CMV (Ab-/Tc+;28%). To determined whether the type of immune response to CMV infection influenced the prevalence of coronary artery disease (CAD), we studied 238 patients being evaluated the presence of CAD. We found that, in the total of study cohort, the most common of the four categories of immune response was an immunodominant humeral response (Ab+/Tc-; 42%), and the least common was an immunodominant cellular response (Ab-/Tc+; 9%). Twenty-three percent of our patients had a combined humeral and cellular (Ab+/Tc+) response, and 26% had no apparent immune response to CMV (Ab-/Tc-). Most importantly, we demonstrated that the type of immune response to CMV influences CAD prevalence in women, who had similar types of immune responses to CMV infection as those in the total cohort. The prevalence of CAD was 13% in Ab-/Tc- women . It was 5 times higher in Ab+/Tc- (68%, P=0.0005) and in Ab+/Tc+ women (64%, P=0.003). The prevalence of CAD (25%) in the women with an immunodominant cellular response (Ab-/Tc+) was not different from Ab-/Tc- group, but was significantly lower than that of Ab+/Tc- group (P=0.016). There were no differences in age, smoking, diabetes, hypercholesterolemia or hypertension among the women with different types of immune response to CMV infection (all P<0.1). Although our studies showed no relationship between the type of immune response and CAD prevalence in men, we demonstrated that a considerable host variability exists in the inflammatory responses to CMV infection, as reflected by elevated C-reactive protein (CRP) levels. We found that, in men, the mean CRP value was significantly higher in men with CAD than in those without CAD (0.86+/-0.05 vs. 0.59+/-0.07 mg/dL, P=0.01). Seventy-six percent of men with CAD had CRP levels <0.5 mg/dL, vs. 50% of those without CAD (P=0.004). When adjusted for traditional CAD risk factors and CMV seropositivity by multivariate analysis, we found that elevated CRP level was a significant independent predictor of CAD (odds ratio=3.0, P=0.02). Although CMV seropositivity was not significantly associated with CAD in men, CMV seropositivity was an independent determinant of CRP levels on multivariate analysis (r=0.4, P=0.05). Therefore, our studies suggest that CMV infection contributes to the development of CAD. However, the mechanisms whereby CMV predisposes to CAD in men and women are different. In men, CMV mainly appears to contribute to CAD risk insofar as it predisposes to inflammation. In women, CMV is an independent risk factor for CAD. Thus, our observations raise the possibility of novel therapeutic strategies for the prevention or treatment of atherosclerosis. It might be possible to alter disease outcome favorably through the use of vaccines or cytokine-based strategies designed to change an inflammatory response or immune type directed against a causally relevant pathogen from one that conveys disease susceptibility to one that enhances resistance. This concept would be especially attractive if similar associations between CAD and infection with other pathogens, such as Chlamydia pneumoniae and Helicobacter pylori, and with the immune response to these pathogens, were additionally demonstrated.